Serially assessed bisphenol A and phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: A longitudinal cohort study

Abstract

Background Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Methods and findings Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2′-deoxyguanosine [8-OHdG] and F 2 -isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F 2 -isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z- score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F 2 -isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F 2 -isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m 2 (95% CI: −0.75, −0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. ...

Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors

“…The long-term effects of short-lived EDCs should be thus evaluated by the incorporation of both baseline and serial assessments of BPA levels in longitudinal studies in relation to metabolic outcomes. Studies have recently applied a time-averaged statistical approach to derive the cumulative average exposure to BPA [ 54 ]. To further assess chronic exposure, the health outcomes in occupationally exposed individuals can be compared to environmentally exposed individuals.…”

A Scoping Review of Life-Course Psychosocial Stress and Kidney Function

“…These psychosocial stress factors have previously been associated with adverse perinatal effects that include low birth weight, small for gestational age, prematurity, neurodevelopment, metabolic, cardiovascular, and respiratory alterations [ 6 , 7 , 40 , 41 , 42 , 43 ]. Additionally, it is essential to acknowledge that exposure to chemical substances may have a synergistic effect in perinatal outcomes when pregnant women are co-exposed to psychosocial stressors and other environmental toxicants, both individually and at a community level [ 44 , 45 , 46 ]. As is the case for preterm birth, wherein concomitant exposure to adverse life events (e.g., poverty, racism, inequitable access to healthcare) as well as an individual’s exposure to environmental toxicants (e.g., air pollution, metals, some pesticides, or phthalates), may also damage developing kidneys, reducing nephron endowment over the life course [ 38 , 47 , 48 ].…”

Bisphenol a Exposure and Kidney Diseases: Systematic Review, Meta-Analysis, and NHANES 03–16 Study

“…Secondly, the relationship between BPA and the eGFR has also been studied in the studies by You et al [35], Malits et al [36], Lee et al [33], Jacobson et al [37], and Kang et al [34]. Malits et al [36], Lee et al [33], Jacobson et al [37], and Kang et al [34] offer enough data, but in the work of You et al [35], OR must be calculated from the standard mean difference of its two study groups. They use the Modification of Diet in Renal Disease (MDRD-4) and the "Chronic Kidney Disease Epidemiology Collaboration" (CKD-EPI) equations to estimate GFR (Figure 3).…”

“…They determined a 0.28 mg/g ACR increase for each log unit increase in urinary BPA after performing multinomial regression models. Within the other group can be found the works of You et al [35], Malits et al [36], Kang et al [32], Lee et al [33], Jacobson et al [37], and Kang et al [34]. The first of them [35], studied kidney function by calculating the eGFR using the MDRD and CKD-EPI equations.…”

“…Lee et al [33] determined a statistically significant negative relationship between BPA and eGFR in the general Korean population. Jacobson et al [37] observed, in children with kidney disease, a negative relationship between BPA and eGFR (linear mixed-effects models). Interestingly, they also determined a positive and statistically significant relationship between urinary BPA and kidney damage markers, such as NGAL and KIM-1.…”